Leishmania is a genus of Trypanosomatid protozoa, and is the parasite responsible for the disease leishmaniosis which is a major and severe parasitic disease that affects humans, canines, and to a lesser degree, felines. Leishmania species are spread through sandflies of the genus Phlebotomus in the Old World and of the genus Lutzomyia in the New World. In humans, there are several forms of the disease named by their clinical presentation including cutaneous, mucocutaneous or visceral leishmaniosis caused by a variety of species of Leishmania. The predominant cause of canine leishmaniosis is L. infantum (sometimes referred to as L. chagasi in New World) which causes both visceral and cutaneous forms in dogs and the clinical distinction of the form of disease is less important. L. infantum is a cause for all forms of disease in humans and dogs serve as the primary reservoir for human infections caused by this species (Baneth G et al). L. infantum is widely distributed in temperate and subtropical countries of Southern Europe, Africa, Asia, South America and Central America, and the incidence of L. infantum is expanding geographically (Dantas-Torres F et al., 2012, Baneth G et al., Peterson CA et a/.2009, Ready PD et al., Miro G et al. 2010).
Canine leishmaniosis is a slowly progressive disease that can take years to become clinically apparent (McConkey S E et al., 2002). Signs are frequently non-specific and diagnosis in non-endemic regions is often overlooked. Some dogs appear naturally resistant to this parasite and can act as asymptomatic reservoir hosts (Grosjean N L et al., 2003). Approximately 10% of dogs residing in endemic areas actually develop clinical disease (Lindsay D S et al., 2002). Some of the more frequently reported clinical signs of leishmaniosis include skin lesions, listlessness, fatigue and exercise intolerance coupled with anorexia and weight loss that eventually culminate as wasting disease with chronic renal failure as the main cause of mortality (McConkey S E et al.; Solano-Gallego L et al). These signs may or may not be accompanied by fever, local or generalized lymphadenopathy, and hepatosplenomegaly (Grosjean N L et al., 2003; Lindsay D S et al., McConkey S E et al.; Martinez-Subiela S et al., 2002). Articular involvement is also fairly common and may present as lameness with swollen joints or simply as a stiff gait. Less common findings include ocular lesions (<5%), chronic diarrhea (30%) and long, deformed brittle nails (20%) referred to as onychogryphosis (Lindsay D S et al., Slappendel R J et al.).
Currently there are three drugs specifically approved for the treatment of canine leishmaniosis in Europe: N-methyl-glucamine (meglumine) antimoniate (GLUCANTIME®, Merial), miltefosine (MILTEFORAN®, Virbac), and domperidone (LEISHGUARD®, Esteve, Spain). The most commonly recommended treatment protocols for dogs with clinical leishmaniosis by European veterinary groups are meglumine antimoniate or miltefosine in combination with allopurinol, a xanthine oxidase inhibitor with anti-leishmania properties (Oliva G et al., Solano-Gallego L et al.). Domperidone is an antidopaminergic compound that has been demonstrated to enhance the cell mediated immune response to leishmania infection in dogs. Even in combination with allopurinol, both meglumine antimoniate and miltefosine do not result in a parasitologic cure 100% of the time, and relapse of disease is common (Mana L et al., Mateo M. et al., Solano-Gallego L et al., Oliva G et al.) Domperidone is indicated for the prevention or treatment of mild to moderate cases of canine leishmaniosis and its use in combination therapies is under investigation (Solano-Gallego L et al.). In addition to the inability to produce a parasitologic cure, all of the recommended treatment protocols are associated with significant side effects: meglumine antimoniate is associated with nephrotoxicity and cellulitis at the injection site, miltefosine is associated with vomiting and diarrhea, and allopurinol can induce xanthine urolithiasis (Solano-Gallego L et al.).
Mass detection of seropositive dogs followed by culling and/or drug treatment or the mass application of deltamethrin-impregnated collars were shown to have an impact in reducing human and canine leishmaniosis prevalence in endemic areas of Southern Europe, Africa, and Asia (Maroli et al., 2001; Mazloumi Gavgani A. S. et al., 2002), although the efficacy of eliminating seropositive canines has been debated (Dietze R et al., 1997; Moreira Jr. et al., 2004). These control measures are either considered unacceptable, expensive or not effective (Gradoni L. et al., 2005). Encouragingly, Susan Wyllie (Sci Transl. Med 4, 119, 2012) recently reported fexinidazole was able to suppress infection due to L. donovani infection (leishmania species affecting humans). However, it is not known whether the drug will work against the predominantly canine leishmania strain, L. infantum, nor is it known whether complete elimination (also referred to herein as “curing”) of canine leishmaniosis infection is possible. “Elimination” or “curing” is deemed to be “substantially complete” if the leishmaniosis clinical symptoms do not return after drug treatment (post-drug treatment re-exposure to the parasites notwithstanding). Moreover, the mouse model does not faithfully recapitulate canine Leishmania infection. For example, mice show no clinical signs and do not die from parasite, whereas dogs do. Thus, a skilled person cannot, with any certainty, expect that a treatment method capable of reducing the number of L. donovani parasites in mice, will also prevent clinical signs and death—caused by L. infantum—in a dog. Adding to the uncertainty is that Leishmania parasites are notoriously resistant to drug treatment, and many drugs useful in combating other diseases (including diseases caused by related protozoans) are not efficacious against Leishmania. For example, Leishmania parasites are well-known to reduce drug concentration by both decreasing drug uptake and by increasing drug efflux/sequestration (Haldar, 2011). Finally, anti-leishmaniosis drugs are extremely toxic, and thus poorly tolerated by humans and non-human animals alike.
Thus, there remains a need for effective and efficient methods of eradicating or curing leishmania infections.